Lomustine With and Without Reirradiation for First Progression of Glioblastoma: a Randomized Phase III Study

NCT05904119 | Recruiting Phase 3 DMC

• 1 other identifier: EORTC-2227-BTG
• Study Type: interventional
• Target: 411
• Locations: 11 countries
• Sites: 43

Brief Summary

Despite comprehensive multimodal treatment of newly diagnosed glioblastoma, almost all patients suffer from tumour relapse. Currently, no standard of care exists to treat these tumour relapses. Treatment options include repeated surgery (if feasible), systemic therapy (bevacizumab, lomustine, temozolomide re-challenge), reirradiation and best supportive care. Currently, the superiority of combined chemoradiation versus chemotherapy alone remains unproven. Given that lomustine is the standard chemotherapeutic agent for the treatment of recurrent glioblastoma in Europe and the unclear efficacy of reirradiation, we want to explore whether combining lomustine and reirradiation may be a better treatment than lomustine alone. The results of the prospective randomized trial proposed here should demonstrate a significant improvement in overall survival when lomustine is combined with reirradiation in patients with recurrent glioblastoma compared to lomustine alone without adversely affecting quality of survival. The trial will be stopped based on overall survival in a preplanned futility and efficacy interim analysis.

Conditions

First Progression of Glioblastoma

Keywords

First progression; Glioblastoma; Phase III; Lomustine; Reirradiation

Outcome Measures

Primary Outcomes (1)

• Overall Survival (OS)

  Defined as the number of days from date of enrolment to the date of death due to any cause

  From the date of enrolment up to the date of death, assessed up to 40 months after first patient is enrolled

Secondary Outcomes (7)

• Progression Free Survival (PFS)

  From the date of enrolment up to the date of first objective progression or the date of death whichever occur first, assessed up to 40 months after first patient is enrolled

• Health-related Quality of Life (HRQoL)

  From the date of enrolment until disease progression, assessed up to 40 months after first patient is enrolled

• Toxicity profile of lomustine plus reirradiation

  From the date of enrolment until end of study treatment 30 (± 7 days) after last dose, assessed up to 40 months after first patient is enrolled

• Neurocognitive functioning of lomustine pus reirradiation

  From the date of enrolment until end of study treatment 30 (± 7 days) after last dose, assessed up to 40 months after first patient is enrolled

• To transform self-reported quality of life data from the QLQ-C30 into health utility values, ready to be used in subsequent health economic analyses.

  From the date of enrolment until disease progression, assessed up to 40 months after first patient is enrolled

Other Outcomes (1)

• To assess health-related quality of life over time based on the results of 3 different scales (QLQ-C30, QLQ-BN20 and the item list (IL46)).

  From the date of enrolment until disease progression, assessed up to 40 months after first patient is enrolled

Study Arms (2)

Control group

ACTIVE COMPARATOR

Lomustine alone

Drug: Lomustine

Experimental group

EXPERIMENTAL

Lomustine plus reirradiation

Drug: Lomustine; Radiation: Reirradiation

Interventions

Lomustine DRUG

Oral administration of Lomustine

Control group; Experimental group

Reirradiation RADIATION

Given at least 6 months after the end of prior radiotherapy

Experimental group

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Before patient's enrolment, written informed consent must be given according to ICH/GCP, and national/local regulations.
• Patients with first progression or recurrent glioblastoma after standard chemoradiotherapy (any treatment other than use of nitroureas) having occurred at least 6 months after the end of prior radiotherapy
• Measurable disease according to RANO criteria with a maximum tumour diameter of 5 cm (local investigator assessment)
• In case of surgery for recurrence: fully recovered from surgery, confirmation of recurrence by histology, and patient fit for treatment as per local investigator assessment.
• Histologically proven diagnosis of glioblastoma, IDH wildtype per WHO 2021 classification and local assessment of tissue from diagnosis or recurrence
• Initial treatment of newly diagnosed glioblastoma by maximal safe resection and postsurgical concurrent conventionally fractionated or abbreviated (minimum 15 fractions) chemoradiotherapy with or without maintenance chemotherapy with temozolomide (patient must have received at least one dose)
• Stable or decreasing dose of steroids for 7 days prior to enrolment
• Age ≥ 18 years
• WHO Performance status of 0-2
• Women of childbearing potential (WOCBP) must have a negative serum pregnancy test within 7 days prior to the first dose of study treatment.
• Patients of childbearing / reproductive potential must agree to use adequate birth control measures during the study treatment period and for at least 6 months after the last dose of study treatment. A highly effective method of birth control is defined as a method which results in a low failure rate (i.e., less than 1% per year) when used consistently and correctly.
• Female subjects who are breast feeding should discontinue nursing prior to the first dose of study treatment and until 6 months after the last study treatment.
• Non-sterile males must use contraception during treatment and for 6 months after the last dose.
• Non-sterile males must avoid sperm donation for the duration of the study and for at least 6 months after the last dose of study treatment.

You may not qualify if:

• Any prior anticancer treatment for recurrent glioblastoma (except surgery)
• Significant reduction in thrombocyte and/or leukocyte counts as well as severe renal impairment according to investigator's opinion
• History or present acute leukaemia or any myeloid disease
• Known hypersensitivity to the active components or excipients of lomustine
• Known coeliac disease or wheat allergy
• Live attenuated vaccine in the 3 months prior to lomustine initiation
• Any serious or uncontrolled medical condition (e.g., infections, chronic alcoholism, drug addiction) or abnormality, in the judgment of the investigator that prohibits obtaining informed consent, safe participation and study completion
• Known contraindication to imaging tracer or any product of contrast media and Magnetic Resonance Imaging (MRI) contraindications
• Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be assessed and discussed with the patient before the enrolment in the trial.

Sponsors & Collaborators

• Swiss Cancer Institute: collaborator
• European Organisation for Research and Treatment of Cancer - EORTC: lead

Study Sites (43)

A.O Landeskrankenhaus - Innsbruck Universitaetsklinik

Innsbruck, 6020, Austria

RECRUITING

Kepler University Hospital - Neuromed campus

Linz, 4020, Austria

RECRUITING

Universitaetsklinikum Wien - AKH unikliniken

Vienna, Austria

RECRUITING

AZORG

Aalst, 9300, Belgium

RECRUITING

Cliniques Universitaires Saint-Luc

Brussels, 1200, Belgium

RECRUITING

Universitair Ziekenhuis Gent

Ghent, 9000, Belgium

RECRUITING

Grand Hopital de Charleroi - Site Les Viviers

Gilly, 6060, Belgium

RECRUITING

U.Z. Leuven - Campus Gasthuisberg

Leuven, 3000, Belgium

RECRUITING

Masaryk Memorial Cancer Institute

Brno, Czechia

RECRUITING

Aarhus University Hospitals - Region Midtjylland - Aarhus University Hospital-Skejby

Aarhus, 8200, Denmark

RECRUITING

CHU d'Amiens - CHU Amiens Picardie - Site Sud

Amiens, 80054, France

RECRUITING

CLCC - Jean Perrin

Clermont-Ferrand, 63000, France

RECRUITING

CHRU de Lille

Lille, 59037, France

RECRUITING

CHU de Lyon - CHU Lyon - Hopital neurologique Pierre Wertheimer

Lyon, France

RECRUITING

Institut du Cancer de Montpellier

Montpellier, France

RECRUITING

CHU de Nice - Hôpital Pasteur

Nice, 06000, France

RECRUITING

Assistance Publique Hopitaux Paris- APHP - APHP Sorbonne Univ - Hopital la Pitie-Salpetriere (233)

Paris, 75013, France

RECRUITING

Assistance Publique Hopitaux Paris- APHP - APHP Nord - Univ De Paris Cite - Hop. Saint Louis

Paris, France

RECRUITING

Institut de Cancerologie de l´Ouest (ICO) - Saint Herblain

Saint-Herblain, 44805, France

RECRUITING

Univ. Knappschaft Krankenhaus Bochum

Bochum, 44892, Germany

RECRUITING

Universitaetsklinikum Koeln

Cologne, 50937, Germany

RECRUITING

Universitaetsklinikum Erlangen-Schwabachanlage

Erlangen, Germany

RECRUITING

Universitaetsklinikum Heidelberg - UniversitaetsKlinikum Heidelberg - Head Hospital

Heidelberg, 69120, Germany

RECRUITING

Universitätsklinikum Leipzig-Klinik für Strahlentherapie und Radioonkologie

Leipzig, 04103, Germany

RECRUITING

Ludwig-Maximilians-Universitaet Muenchen - Campus Grosshadern

Munich, 81377, Germany

RECRUITING

Universitaetsklinikum Regensburg

Regensburg, Germany

RECRUITING

Universitaetsklinikum Tuebingen- Crona Kliniken

Tübingen, 72076, Germany

RECRUITING

IRCCS-Ospedale Bellaria-Bologna

Bologna, 40139, Italy

RECRUITING

ULSS 9 Scaligera Veneto - Azienda Unita Locale Socio-Sanitaria N. 9-Mater Salutis Hospital

Legnago, 37045, Italy

RECRUITING

Istituto Clinico Humanitas

Milan, 20089, Italy

RECRUITING

IRCCS - Istituto Oncologico Veneto

Padua, 35128, Italy

RECRUITING

Azienda ospedaliero Univ Policlinico Umberto I

Roma, 00161, Italy

RECRUITING

Medisch Spectrum Twente

Enschede, 7512 KZ, Netherlands

RECRUITING

Leiden University Medical Centre

Leiden, Netherlands

RECRUITING

Erasmus MC

Rotterdam, Netherlands

RECRUITING

ETZ Tilburg - ETZ - St. Elisabethziekenhuis

Tilburg, 5022, Netherlands

RECRUITING

Oslo University Hospital - Radiumhospitalet

Oslo, NO 0379, Norway

RECRUITING

St Olavs University Hospital - St. Olavs Hospital, Trondheim University Hospital

Trondheim, NO 7030, Norway

RECRUITING

Hospital Germans Trias i Pujol (Institut Catala D'Oncologia)

Badalona, Barcelona, Spain

RECRUITING

Institut Catala d'Oncologia - ICO Badalona - Hospital Germans Trias i Pujol (Institut Catala D'Oncologia) (381)

Badalona, 08916, Spain

RECRUITING

ICO L'Hospitalet - Hospital Duran i Reynals (Institut Catala D'Oncologia)

L'Hospitalet de Llobregat, 08908, Spain

RECRUITING

Hospital Universitario 12 de Octubre

Madrid, 28041, Spain

RECRUITING

Oncology Institute of Southern Switzerland (IOSI) - Ospedale San Giovanni

Bellinzona, 6500, Switzerland

RECRUITING

Related Publications (1)

• Preusser M, Kazda T, Le Rhun E, Sahm F, Smits M, Gempt J, Koekkoek JA, Monti AF, Csanadi M, Pitter JG, Bulbek H, Fournier B, Quoilin C, Gorlia T, Weller M, Minniti G; European Organisation for Research, Treatment of Cancer (EORTC) Brain Tumor Group. Lomustine with or without reirradiation for first progression of glioblastoma, LEGATO, EORTC-2227-BTG: study protocol for a randomized phase III study. Trials. 2024 Jun 7;25(1):366. doi: 10.1186/s13063-024-08213-7.

  PMID: 38849943 DERIVED

MeSH Terms

Conditions

Glioblastoma

Interventions

Lomustine; Re-Irradiation

Condition Hierarchy (Ancestors)

Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Nitrosourea Compounds; Urea; Amides; Organic Chemicals; Nitroso Compounds; Radiotherapy; Therapeutics; Retreatment

Study Officials

• Matthias Preusser, Prof.

  EORTC Study Coordinator

  PRINCIPAL INVESTIGATOR

• Giuseppe Minniti, Dr.

  EORTC Study Coordinator

  PRINCIPAL INVESTIGATOR

Central Study Contacts

EORTC

CONTACT

+3227741611; eortc@eortc.org

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 23, 2023
• First Posted: June 15, 2023
• Study Start: March 15, 2024
• Primary Completion (Estimated): September 1, 2027
• Study Completion (Estimated): February 1, 2028
• Last Updated: February 17, 2026

Record last verified: 2026-02

Locations

CZ (1); NL (4); FR (9); ES (4); CH (1); BE (5); AU (3); DE (8); NO (2); IT (5); DK (1)